The present invention concerns methods for transdermal delivery or transport of therapeutic agents, typically through iontophoresis. Herein the terms "iontophoresis" and "iontophoretic" are used to refer to methods and apparatus for transdermal delivery of therapeutic agents, whether charged or uncharged, by means of an applied electromotive force to an agent-containing reservoir. The particular therapeutic agent to be delivered may be completely charged (i.e., 100% ionized), completely uncharged, or partly charged and partly uncharged. The therapeutic agent or species may be delivered by electromigration, electroosmosis or a combination of the two. Electroosmosis has also been referred to as electrohydrokinesis, electro-convection, and electrically-induced osmosis. In general, electroosmosis of a therapeutic species into a tissue results from the migration of solvent, in which the species is contained, as a result of the application of electromotive force to the therapeutic species reservoir.
As used herein, the terms "iontophoresis" and "iontophoretic" refer to (1) the delivery of charged drugs or agents by electromigration, (2) the delivery of uncharged drugs or agents by the process of electroosmosis, (3) the delivery of charged drugs or agents by the combined processes of electromigration and electroosmosis, and/or (4) the delivery of a mixture of charged and uncharged drugs or agents by the combined processes of electromigration and electroosmosis.
Iontophoresis, according to Dorland's Illustrated Medical Dictionary, is defined to be "the introduction, by means of electric current, of ions of soluble salts into the tissues of the body for therapeutic purposes." Iontophoretic devices have been known since the early 1900's. British patent specification No. 410,009 (1934) describes an iontophoretic device which overcame one of the disadvantages of such early devices known to the art at that time, namely the requirement of a special low tension (low voltage) source of current which meant that the patient needed to be immobilized near such source. The device of that British specification was made by forming a galvanic cell from the electrodes and the material containing the medicament or drug to be transdermally delivered. The galvanic cell produced the current necessary for iontophoretically delivering the medicament. This ambulatory device thus permitted iontophoretic drug delivery with substantially less interference with the patient's daily activities.
More recently, a number of United States patents have issued in the iontophoresis field, indicating a renewed interest in this mode of drug delivery. For example, Vernon et al. U.S. Pat. No. 3,991,755; Jacobsen et al. U.S. Pat. No. 4,141,359; Wilson U.S. Pat. No. 4,398,545; and Jacobsen U.S. Pat. No. 4,250,878 disclose examples of iontophoretic devices and some applications thereof. The iontophoresis process has been found to be useful in the transdermal administration of medicaments or drugs including lidocaine hydrochloride, hydrocortisone, fluoride, penicillin, dexamethasone sodium phosphate and many other drugs. Perhaps the most common use of iontophoresis is in diagnosing cystic fibrosis by delivering pilocarpine salts iontophoretically. The pilocarpine stimulates sweat production; the sweat is collected and analyzed for its chloride content to detect the presence of the disease.
In presently known iontophoresis devices, at least two electrodes are used. Both of these electrodes are disposed so as to be in intimate electrical contact with some portion of the skin of the body. One electrode, called the active or donor electrode, is the electrode from which the ionic substance, agent, medicament, drug precursor or drug is delivered into the body via the skin by iontophoresis. The other electrode, called the counter or return electrode, serves to close the electrical circuit through the body. In conjunction with the patient's skin contacted by the electrodes, the circuit is completed by connection of the electrodes to a source of electrical energy, e.g., a battery. For example, if the ionic substance to be driven into the body is positively charged, then the positive electrode (the anode) will be the active electrode and the negative electrode (the cathode) will serve to complete the circuit. If the ionic substance to be delivered is negatively charged, then the cathodic electrode will be the active electrode and the anodic electrode will be the counter electrode.
Alternatively, both the anode and the cathode may be used to deliver drugs of opposite charge into the body. In such a case, both electrodes are considered to be active or donor electrodes. For example, the anodic electrode can drive positively charged ionic substances into the body while the cathodic electrode can drive negatively charged ionic substances into the body.
Furthermore, existing iontophoresis devices generally require a reservoir or source of the ionized or ionizable species (or a precursor of such species) which is to be iontophoretically delivered or introduced into the body. Examples of such reservoirs or sources of ionized or ionizable species include a pouch as described in the previously mentioned Jacobsen U.S. Pat. No. 4,250,878, a pre-formed gel body as disclosed in Webster U.S. Pat. No. 4,382,529 and a generally conical or domed molding of U.S. Pat. No. 4,722,726 to Sanderson et al. Such drug reservoirs are electrically connected to the anode or the cathode of an iontophoresis device to provide a fixed or renewable source of one or more desired species or agents.
Recently, the transdermal delivery of peptides and proteins, including genetically engineered proteins, by iontophoresis has received increasing attention. Generally speaking, peptides and proteins being considered for transdermal or transmucosal delivery have a molecular weight ranging between about 500 to 40,000 daltons. These high molecular weight substances are usually too large to diffuse passively (i.e., without electromotive force) through skin at therapeutically effective rates. Since many peptides and proteins carry either a net positive or net negative charge and because of their inability to diffuse passively through skin, they are considered likely candidates for iontophoretic delivery as defined herein.
One of the technical hurdles that, heretofore, has not been overcome has been the problem of the patient feeling the electrical current applied by the iontophoretic delivery device. In severe cases (e.g., at high current densities), the sensation can be painful. Particularly during the moments of drug delivery shortly after application of the iontophoretic drug delivery device to a patient's skin, complaints of pain, stinging, itching, tingling, prickliness, burning, or other unwanted or undesired skin sensation have been voiced. All of these various responses are to be considered forms of sensation within the contemplation of the present invention.
This technical hurdle has been addressed in the art. In an early article, H. Molitor et al. in "Experimental Studies on the Causes and Prevention of Iontophoretic Burns", 198 Am. J. Med. Sci, 778-785 (1939) reported on the occurrence of burns caused by pH changes, and that there was a definite relationship between pain and irritation and such pH changes in the skin.
U.S. Pat. No. 4,211,222 to Robert Tapper suggests that pain or tingling due to passage of current may be reduced by the use of a larger positive electrode. The method of the '222 Tapper patent employs a porous intervenor material between the electrode and the patient's skin. The intervenor has a thickness which is very large in relation to the thickness of the patient's skin between the electrode and the patient's skin.
U.S. Pat. No. 4,340,047 also to Robert Tapper discloses a self-treatment iontophoretic treatment apparatus. The '047 patent suggests the gradual imposition of a treatment period to reduce the possibility of electrical shock. A delay means is employed in the device of the '047 patent to impose the drug treatment current gradually when the device is activated by placing a load across its terminals.
U.S. Pat. No. 4,406,658 to Gary A. Lattin et al. discloses an iontophoretic device in which the polarity of the electrodes is reversible. As disclosed by Lattin et al. current is reduced prior to switching of polarities to avoid the possibly unpleasant sensation of having the polarities change while the device is operating at a therapeutic current level.
J. Bradley Phipps et al. in the abstract of their paper presented to the Controlled Release Society Meeting of August, 1989 describe the effect of "extraneous" ions, that is, ions having the same charge of the drug to be delivered, on the delivery of hydromorphone. The presence of extraneous ions may reduce the efficiency of drug delivery from an iontophoretic delivery device since the extraneous ions compete with the drug ions for carrying current into the body. Phipps et al. accordingly teach the desirability of minimizing the amount of extraneous ions available to compete with the species or agent to be delivered. Extraneous ions whose effect was described in the Phipps et al. paper include lithium, calcium, potassium, sodium and magnesium. Phipps et al. make no mention of stinging or other skin sensation(s), encountered in the delivery of the desired or extraneous ions.
None of the above references, alone or in combination, disclose or suggest the present invention.